It is particularly preferred to employ Staphylococcal genes and gene products as targets for the development of antibiotics. The Staphylococci make up a medically important genera of microbes. They are known to produce two types of disease, invasive and toxigenic. Invasive infections are characterized generally by abscess formation effecting both skin surfaces and deep tissues. S. aureus is the second leading cause of bacteremia in cancer patients. Osteomyelitis, septic arthritis, septic thrombophlebitis and acute bacterial endocarditis are also relatively common. There are at least three clinical conditions resulting from the toxigenic properties of Staphylococci. The manifestation of these diseases result from the actions of exotoxins as opposed to tissue invasion and bacteremia. These conditions include: Staphylococcal food poisoning, scalded skin syndrome and toxic shock syndrome.
The frequency of Staphylococcus aureus infections has risen dramatically in the past 20 years. This has been attributed to the emergence of multiply antibiotic resistant strains and an increasing population of people with weakened immune systems. It is no longer uncommon to isolate Staphylococcus aureus strains which are resistant to some or all of the standard antibiotics. This has created a demand for both new anti-microbial agents and diagnostic tests for this organism.
Div1b (designated ftsQ in E.coli and div1b in B.subtilus) is an essential gene involved in bacterial cell division. E.coli FtsQ has been identified as a Div1B homolog, being 18% identical and 44% similar (Harry et al., (1994) Gene 147 85-89). It has been shown in E.coli that FtsQ is required through out the whole process of septum formation during cell division. FtsQ is a simple cytoplasmic membrane protein with approx 21 amino acids in the cytoplasmic domain, 25 amino acids in the cytoplasmic membrane and approx. 230 amino acids in the periplasmic domain (Carson et al., 1991, J. Bacteriol. 173: 2187-2195). It is estimated that FtsQ is present at about 20 copies/cell (Carson et al., 1991, J. Bacteriol. 173: 2187-2195). Div1B of B.subtilus 168 is also essential for viability at 37.degree. C. and above and is required at all temperatures for the normal rate of cell division (Beall and Lutkenhaus, 1989, J.Bacteriol. 171: 6821-6834). An FtsQ-MalG fusion protein, where the cytoplasmic and the most of the membrane spanning regions of FtsQ were replaced with similar domains of Mal G, has been shown to complement an FtsQ temperature sensitive mutant. This suggests that the cytoplasmic and membrane spanning regions of FtsQ may not be required for protein function (Dai et al., 1996, 178, 1328-1334). However, a portion of the membrane spanning region of FtsQ was required to transport the protein to the periplasm. In contrast, a report by Guzman et al., 1997 (J. Bacteriol. 179, 5094) suggests that only the membrane-spanning segment of ftsQ can be replaced and the cytoplasmic domain is essential for function. Descoteaux and Drapeau et al., 1987 (J. Bacteriol 169, 1938) have suggested that FtsQ may interact with FtsZ. The biochemical function of FtsQ is not known.
Clearly, there is a need for factors, such as the novel compounds of the invention, that have a present benefit of being useful to screen compounds for antibiotic activity. Such factors are also useful to determine their role in pathogenesis of infection, dysfunction and disease. There is also a need for identification and characterization of such factors and their antagonists and agonists which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptides of the invention have amino acid sequence homology to a known FtsQ in E.coli and Div1bin B.subtilus protein.